Synergism Of Lurbinectedin (Pm01183) Combined With 5-Fluorouracil (5-Fu): In Vitro And In Vivo Studies

Background: Lurbinectedin (PM01183), a new synthetic tetrahydroisoquinoline alkaloid, is a minor groove specific DNA binder that interacts directly with specific factors involved in DNA repair and transcription pathways. In living cells, PM01183-DNA adducts stall replication and transcription giving rise to double strand breaks, inducing accumulation of cells in the S-phase of the cell cycle and triggering apoptosis. In both the ongoing phase II trials (pancreas and platinum-resistant ovarian cancer) the first stage was concluded with positive results in clinical activity, ensuring the continuity of the trials. Also, phase I trials in combination with doxorubicin and gemcitabine as well as in advanced acute leukemia are ongoing. The synergism (in vitro and in vivo) of PM01183 combined with 5-Fluorouracil (5-FU) is presented here. Material and Methods: In vitro: The combination of PM01183+5-FU was tested in 12 different tumor cell lines: lung, sarcoma, melanoma, prostate, pancreas, gastric, ovarian, hepatocarcinoma, colon, kidney, glioma and breast cancer. In vivo: Athymic mice were implanted with HGC-27 (gastric) cancer cells. Mice bearing tumors (ca. 150 mm 3 ) were allocated to 13 groups (N=6-8/group): placebo; PM01183 at MTD (0.180 mg/kg [0.54 mg/m 2 ]), 0.75MTD, 0.5MTD and 0.25MTD; 5-FU at MTD (50.0 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; and, PM01183+5-FU at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) MTDs. In separate experiments, mice bearing SW1990 (pancreas) or HT-29 (colon) tumors received treatments (single or combination) at the MTD levels. All treatments were given intravenously once per week during the placebo-treated survival time. The combination index (CI) was determined by the CI-isobol method in the HGC-27 experiments (in vitro or in vivo). Statistical differences for the antitumor effect recorded between groups were determined using two-tailed Mann-Whitney U test. Results: In vitro, a synergistic effect was seen in gastric (HGC-27) and colon (HT29) cells. The recorded in vivo antitumor effect indicated synergism (CI Conclusion: In vitro, the combination of PM01183+5-FU showed a synergistic effect in gastric and colon tumor cell lines. In agreement, in vivo synergism was seen after the treatment with PM01183+5-FU of mice bearing gastric, colon or pancreas xenografted tumors. Citation Format: Pablo Aviles, Maria Jose Guillen, Carlos Galmarini, Luis Francisco Garcia, Raquel Lopez, Praxedes Nunez, Victoria Moneo, Carmen Cuevas. Synergism of lurbinectedin (PM01183) combined with 5-fluorouracil (5-FU): in vitro and in vivo studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5498. doi:10.1158/1538-7445.AM2013-5498